1. Field of the Invention
The present invention relates to an antibody or antibody fragment that binds to 1,4,7,10-tetrazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA),which is bound to an alkyl-amino group through one of its pendant carboxyl groups.
2. Related Art
Multi-specific antibodies (msAbs) offer the possibility of improved efficacy in the delivery of radionuclides using antibody targeting. Radionuclide therapy can be more efficacious when the radionuclide is attached to a moiety that is bivalent toward the pretargeted msAb. For example, cross-linking of pretargeted msAb localized at the disease target was effected by a bivalent hapten moiety that carried the radiolabel (Barbet, U.S. Pat. No. 5,256,395). This approach was used for radioimmunotherapy (RAIT) using the radionuclide iodine-131, which had been attached to a suitable bivalent hapten. The recognition system of the second arm of the msAb used in these studies was based on an indium complex of the chelate diethylenetriaminepentaacetic acid (DTPA), which had been doubly attached to a peptide [tyrosyl-lysine], which could be radioiodinated at its tyrosine residue. Ironically, the DTPA-Tyr.Lys(DTPA).OH, although based on and containing chelating agents, was not useful for any radiometals other than indium, since the action of metal binding by metals other than indium effectively destroyed the affinity of the di-DTPA peptide for the recognizing arm of the msAb. To overcome this deficiency, other series of antibodies were raised that did not depend on recognition of a metal complex (Barbet, U.S. Pat. No. 5,274,076). While the reagents made were designed to be hydrophilic in nature, it was mandatory that a chelating agent would also need to be appended to the recognition unit, via a backbone structure of some kind, and this certainly further complicated preparative procedures. In addition, each increase in size of the bivalent hapten could result in a poorer, incomplete clearance pattern in vivo, destroying one of the major advantages of the system based on the DTPA-Tyr.Lys(DTPA).OH recognition peptide.
Known antibodies directed towards other chelating agents are not versatile in recognizing different metal-chelator complexes, nor do they possess high binding affinities to any metal-chelator complex. Antibodies to yttrium-DOTA have been previously prepared using a 2-benzyl-DOTA (a ring-carbon derivatized chelating agent) derivative linked to keyhole limpet hemocyanin (KLH) as immunogen. Several mAbs were described, all of which were IgG1 heavy chain and kappa light chain, with the exception of one that was IgG3 heavy chain and lambda light chain. These anti-DOTA antibodies all had a relatively low affinity (≅2×10−8M), which may not be optimal for use in a pretargeting approach. The mAb selected as best for further study (IgG1 and kappa) was found to bind equally well to both Gd-DOTA and to Y-DOTA, but much less well to other metal complexes such as In-DOTA, Cu-DOTA and Fe-DOTA. The authors ascribed this to the fact that the Y- and Gd-complexes were 9-coordinate [including one water molecule] whereas complexes with In-, Fe- and Cu- were 8-7- and 6-coordinate, respectively. The best binding metals were thought to be best due to the fact that the DOTA ring immunogen has all four amino and all four carboxyl groups available for metal binding, resulting in a higher denticity complex. Metals forming complexes with DOTA of lower denticity did not bind as well to the anti-DOTA-yttrium mAb.
Tissue specificity can be provided by monoclonal antibodies and peptides that target disease-associated antigens and receptors, respectively. However, direct binding of nuclides to these targeting agents often results in agents that have poor biodistribution characteristics, and therefore poor imaging and therapy qualities.
Thus a continuing need exists for a universal antibody directed towards a variety of chelator-metal complexes. The universal antibody will allow the skilled artisan the flexibility of using a single antibody for recognizing and maximizing uptakes of diagnostic and therapeutic nuclides and radionuclides, specifically in high amounts at diseased tissue, compared to surrounding normal tissues. Maximization of radioactivity in this manner can be expected to drastically improve imaging quality during diagnostic techniques and therapeutic ratios during therapy procedures.